OCD is a severe, heritable condition with a lifetime prevalence of about two percent of world populations. The mode of inheritance is incompletely understood but is likely complex, involving multiple genetic loci of small to moderate effect. Our laboratory has played a leading role in studies of OCD and of its genetics for over 15 years, and was one of the founding sites of a multi-center genome-wide study of OCD, the results of which have begun to be reported in the groups publications noted below. In addition, a series of association studies that have identified and evaluated candidate genes in OCD and related disorders is continuing. Several major OCD genetic research results from our Lab in the last year (2008-2009) can be highlighted: 1). In our Labs continuing and collaborative investigations of the role of serotonin and its major genes in OCD and related disorders, we sequenced the promoter region of SLC6A4 to search for additional common possibly functional variants. We discovered that a common single nucleotide polymorphism (SNP), rs25532, strongly modulated SERT expression in several cultured cell lines and in human post-mortem brain cortex. When this SNP and other SLC6A4 SNPs were included in haplotype (i.e., combination) analyses, our group discovered a highly significant association in a large OCD case-control sample (Wendland et al., 2008). In keeping with the hypothesis of increased SERT functioning in OCD, a haplotype containing the higher-expressing variant at each locus was found to be significantly more common in OCD probands than in controls (Wendland et al., 2009). The strong relationship of SLC6A4 variants to different SRI treatment responses in humans represents additional illustrations of gene-based influences on serotonergic pharmacologic responses, i.e., a new SERT-based pharmacogenomics. (2). There is recent evidence from treatment and genetic studies that suggests that another neurotransmitter system besides serotonin may contribute to OCD. This is the brain glutamate system. As with the serotonin system, a brain transporter, the neuronal glutamate transporter, is major regulator of glutamate availability. This glutamate transporter is encoded by the gene SLC1A1. Recent evidence from gene linkage analyses and follow-up candidate gene studies suggested the potential involvement of SLC1A1 in the development of OCD. For these reasons, we undertook a large case-control study that included over 300 OCD probands and over 650 matched controls collected by our Lab. In addition, publicly-accessible SLC1A1 expression and genotype data were evaluated to gain further insights into SLC1A1 function. Six SNPs in or near SLC1A1 were genotyped. We found that gene expression of SLC1A1 is heritable in human cell lines (Wendland et al., 2008). We identified three SNPs in or near SLC1A1 that correlated with gene expression levels. Additionally, two of these SNPs also predicted expression levels in human post-mortem brain tissue, and one SNP was found to have functional consequences in reporter gene studies (Wendland et al., 2009). Two haplotypes at three SNPs, rs3087879, rs301430, and rs7858819, were significantly associated with OCD after multiple testing corrections and contained two of the SNPs associated with expression levels. In addition, another SNP correlating with SLC1A1 gene expression, rs3933331, was associated with an OCD hoarding sub-phenotype as assessed by two independent, validated rating scales for hoarding. Thus, our case-control data corroborate previous smaller family-based studies that, taken together, indicate that SLC1A1, like SLC6A4, is a susceptibility gene for OCD. The expression and genotype database-mining approach that we used provides a new and useful complementary approach to strengthen future candidate gene studies in neuropsychiatric and other disorders which represent a large public health burden. In fact, seven of these disorders, including OCD, were listed in the 2001 World Health Organizations report on the leading causes of years of extended disability among adults. 3). In additional studies of the genetics of OCD, we focused on a gene suggested to be a candidate gene for OCD based on an animal model of some OCD-related compulsive behaviors. Although heritability studies in OCD have shown a 7 times increased risk for first-degree relatives, and twin studies have revealed higher concordance amongst monozygotic twins (85%) compared to dizygotic twins (50%), the identification of the underlying risk-conferring genetic variation by means of classic genetic association studies has proven to be difficult. Recently, it was shown that mice deficient in the postsynaptic synapse-associated protein Sapap3 develop an OCD-like phenotype, which included compulsive grooming and increased anxiety-like behaviors. Interestingly, the phenotype of Sapap3 gene knock-out mice can be rescued by administering SRIs, the most effective group of therapeutic agents for OCD. We hypothesized that variants in the similar human gene, SAPAP3, could contribute to disorders in the OCD spectrum. To test this, we resequenced SAPAP3 in OCD and related disorders in a case-control study, investigating the complete coding region and flanking intronic sequences of SAPAP3 using standard capillary sequencing. We detected seven novel non-synonymous variants. SAPAP3 variants were present in 4.2% of diagnosed OCD and related disorder patients, but only in 1.1% of controls. Thus, we observed a significant case-control association in our moderately sized sample (Zuchner et al., 2009). The majority of changes were missense mutations, while one variant was an in-frame insertion of five amino acids. Modeling analysis of these missense variants identified several variants with likely functional consequences. It is thus possible that a combination of relatively rare susceptibility variants may prove contributory to OCD, as suggested for some other disorders including autism as well as for OCD itself in our prior study of the SLC6A4 uncommon variant, Ileu425Val (Wendland et al., 2008). The combination of the Sapap3 mouse model with compulsive behaviors and our recent, first case-control study of the SAPAP3 gene in humans with OCD demonstrates a role for SAPAP3 in OCD and compulsive behaviors. In fact, a follow-up study recently reported by our colleagues in our collaborative study of siblings who were both affected by OCD found that four of six SNPs investigated in SAPAP3 were nominally associated with specifically-studied grooming disorders, with high genotypic relative risks of 1.6-3.3. All three haplotypes that were identified were nominally associated with at least one grooming disorder. This study thus brings an even sharper focus on OCD subtypes or sub-populations that may be more closely related to specific single genes. Other studies by our group of OCD-related common and uncommon gene variants and also of other OCD subtypes such as hoarding are noted in our list of 2008-2009 publications, below. Also of note is that our group continues to share our 15+ year collection of DNA and phenotype data with collaborators in the Obsessive-Compulsive Disorder Collaborative Genetics Study (OCGS) and the Obsessive-Compulsive Foundation (OCF) groups, as well as other intramural and extramural individual collaborators, thus enhancing the global search for underlying contributions to OCD and related disorders that are of major public health concerns. Twelve papers that were published in the last year that are listed below resulted from these collaborative studies. Other papers that were published that have helped to refine the phenotype for OCD genetic studies are also listed.